Diagnostic performance of plasma pTau217, pTau181, Aß1-42 and Aß1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease.

BACKGROUND: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. METHODS: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A +) or negative (A-) according to CSF Aß1-42/Aß1-40 ratio. Plasma pTau217, pTau181, Aß1-42 and Aß1-40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aß1-42/Aß1-40 ratio. We analyzed the concordance of pTau217 with CSF amyloidosis. RESULTS: Plasma pTau217 and pTau181 concentration were higher in A + than A- while the plasma Aß1-42/Aß1-40 ratio was lower in A + compared to A-. pTau181 and the Aß1-42/Aß1-40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92-0.97) for pTau217, and 0.88 (95% CI 0.84-0.92) for both pTau181 and Aß1-42/Aß1-40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau217 had the highest fold change (× 3.2) and showed high predictive capability in discriminating A + from A-, having 4-7% misclassification rate. The global accuracy of plasma pTau217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. CONCLUSION: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.

Neutrophil to lymphocyte ratio in Alzheimer's disease: A systematic review and meta-analysis.

BACKGROUND: The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of amyloid-ß (Aß) plaques and neurofibrillary tangles has been linked to inflammation and immune dysregulation. The main objective of this systematic review and meta-analysis is to comprehensively evaluate the existing body of research concerning the NLR in the context of Alzheimer's disease (AD) and mild cognitive impairment (MCI). METHOD: We conducted a comprehensive online search and included studies that evaluated the NLR in 1) patients with AD or MCI and 2) healthy control (HC) participants. We also pooled mean and standard deviation (SD) data for each group. RESULTS: Ultimately, 12 studies encompassed 1,309 individuals diagnosed with AD with mean NLR levels of 2.68, 1,929 individuals with MCI with mean NLR levels of 2.42, and 2,064 HC with mean NLR levels of 2.06 were included in this systematic review and meta-analysis. The mean NLR was 0.59 higher in AD patients compared to HC participants (mean difference (MD) = 0.59 [0.38; 0.80]). Similarly, the mean NLR was higher in AD than MCI patients (MD = 0.23 [0.13; 0.33]). Additionally, the mean NLR was higher in individuals with MCI compared to HC participants (MD = 0.37 [0.22; 0.52]). In the subgroup meta-analysis based on the Mini-Mental State Examination (MMSE), AD patients with lower MMSE scores (using a cut-off of 20) exhibited significantly higher mean NLR (3.10 vs. 2.70, with a p-value for subgroup differences < 0.01). CONCLUSION: The NLR, which serves as a marker of peripheral inflammation, shows increased levels in individuals with AD and MCI compared to HC participants. Furthermore, our study indicates that NLR levels are significantly higher in AD than MCI. Additionally, our novel finding suggests significantly higher NLR levels among AD patients with more severe cognitive decline compared to AD patients with less severe cognitive decline. So, it can be concluded that the higher cognitive decline in humans is accompanied by higher NLR levels. Further longitudinal researches are needed to explore more details about the relationship between inflammation and dementia.

Correlation between the Degree of Inflammation and Stress Indicators and Concurrent Cognitive Impairment in Patients with Severe Craniocerebral Injury.

BACKGROUND: Craniocerebral injuries can cause inflammation and oxidative stress, and can have permanent effects on cognitive function. Moreover, over time, excessive expression of inflammatory factors and high levels of oxidative stress will be detrimental to recovery from craniocerebral injury and may exacerbate neurological damage, further damaging neurons and other cellular structures. In this study, we investigated changes in inflammation and stress indicators in patients with severe craniocerebral injuries, and analyzed associations with concurrent cognitive impairment. METHODS: 82 patients with severe craniocerebral injuries admitted to Longyou County People's Hospital during January 2022-June 2023 were selected for retrospective study. Levels of inflammatory factors and the degree of oxidative stress were recorded and compared between the acute and chronic phases. Inflammatory measures included interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP), and oxidative stress indicators included human cortisol (Cor), norepinephrine (NE), and superoxide dismutase (SOD). The patients' cognitive function was evaluated using the Mini-Mental State Examination (MMSE), and the incidence of cognitive impairment was assessed. Spearman's correlation was used to analyze associations between inflammatory and oxidative stress measures and MMSE scores; logistic regression was used to analyze the related factors affecting the patients' concurrent cognitive impairment; and the receiver operating characteristic (ROC) curve was used to test the predictive value of inflammatory and oxidative stress measures on the patients' concurrent cognitive impairment in the acute phase and the chronic phase. RESULTS: Patients had higher levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE, and lower levels of SOD, in the acute phase compared to the chronic phase (p < 0.05). MMSE scores were higher in the acute phase than in the chronic phase (p < 0.05). A total of 50 cases were complicated by cognitive impairment, and the incidence of cognitive impairment was 60.98%. The levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE in the chronic phase were positively correlated with the concurrent cognitive impairment, and the level of SOD was negatively correlated with the concurrent cognitive impairment (p < 0.05). Single-factor analysis showed that age and levels of IL-6, IL-10, TNF-α, CRP, Cor, and NE were higher in the cognitively impaired group than in the cognitively normal group, SOD levels were lower than in the cognitively normal group, and percentages of below-secondary school and frontal lobe damage were higher than those in the cognitively normal group (p < 0.05). Logistic regression analysis showed that below-secondary school, frontal lobe injury, higher levels of IL-6, IL-10, TNF-α, and CRP in the chronic phase, and lower levels of SOD in the chronic phase were all relevant factors affecting the patients' concurrent cognitive impairment. As shown by the ROC curve, the area under the curve (AUC) for the combination of indicators was 0.949, sensitivity was 0.980, and specificity was 0.844. CONCLUSIONS: The incidence of cognitive impairment is higher in patients with severe craniocerebral injury, and the levels of inflammation and oxidative stress, which are not conducive to recovery, are higher in patients in the acute stage. The risk of concurrent cognitive impairment is higher in patients with a lower level of literacy, frontal lobe injury, and high levels of inflammatory factors and oxidative stress in the chronic stage; these indicators, therefore, have a significant predictive effect on the prognosis of the patients.

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: Plasma ß-amyloid-1-42/1-40 (Aß42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB. METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aß42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models. RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aß42/40 ratio (decreased in amyloid abnormal: ß = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: ß = 0.246, 95% CI 0.011-0.481; P-tau231: ß = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (ß = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (ß = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (ß = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without. DISCUSSION: Our study suggests a possible utility of plasma Aß42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

Effects of Baduanjin exercise on cognitive frailty, oxidative stress, and chronic inflammation in older adults with cognitive frailty: a randomized controlled trial.

Background: Oxidative stress and chronic inflammation play an important role in the pathogenesis process of cognitive frailty (CF). Regular Baduanjin exercise could improve cognitive frailty in older adults, but it is unclear whether the effect of Baduanjin exercise on improving CF is mediated by modulating circulating oxidative stress and inflammatory process. Method: A total of 102 community-dwelling older adults with CF were recruited and randomly allocated into a 24-week Baduanjin exercise training group or no specific exercise intervention control group at an equal rate. Cognitive function and physical frailty index were assessed using the Montreal Cognitive Assessment (MoCA) and the Edmonton Frail Scale (EFS), as well as the oxidative stress and inflammatory cytokines were measured at baseline and after intervention. Result: After 24 weeks of intervention, the increased MoCA score (2.51 ± 0.32 points, p < 0.001) and the decreased EFS scores (1.94 ± 0.20 points, p = 0.012) in the Baduanjin group were significantly higher than those in the control group. Serum antioxidant SOD levels were increased by 10.03 ± 4.73 U/mL (p < 0.001), and the prooxidative MDA and 8-iso-PGF2α levels were decreased by -1.08 ± 0.80 nmol/mL (p = 0.030) and -86.61 ± 15.03 ng/L (p < 0.001) in the Baduanjin training group; while inflammatory cytokines IFN-γ, IL-2 and IL-4 levels were increased (1.08 ± 0.33 pg./mL, p = 0.034, 2.74 ± 0.75 pg./mL, p = 0.04 and 1.48 ± 0.35 pg./mL, p = 0.042). In addition, a mediation effect that Baduanjin training improved cognitive ability mediated by an increase of circulating IFN-γ and IL-2 levels were observed in this study. Conclusion: Regular Baduanjin exercise training could improve the cognitive frailty of the community-dwelling older adults with CF, and modulate oxidative stress and inflammatory processes by reducing circulating pro-oxidative MDA and 8-iso-PGF2α levels and increasing anti-oxidative SOD levels, as well as impacting inflammatory cytokines IFN-γ, IL-2, and IL-4 levels. Nevertheless, the mechanism of Baduanjin exercise mediating oxidative stress and inflammatory processes should be cautious to be explained. Clinical trial registration: http://www.chictr.org.cn/index.aspx, ChiCTR1800020341.

The Role of Biomarkers in Predicting Cognitive Impairment in Elderly Patients with Heart Failure.

OBJECTIVE: This study explores the impact of sST2, Growth Differentiation Factor 15 (GDF-15), and clinical factors on cognitive dysfunction in elderly patients with heart failure with reduced ejection fraction (HFrEF). METHODS: A cohort of 101 chronic stable HFrEF patients aged over 65 years old participated in the study. Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) test and the Mini Mental State Examination (MMSE). Levels of sST2, GDF-15, and N-terminal pro b-type natriuretic peptide (NT-proBNP) were also measured. RESULTS: Notably higher levels of NT-proBNP and GDF-15 were observed in the group with cognitive dysfunction, whereas sST2 levels were similar between the groups. The cognitive dysfunction group consisted of older patients. A higher proportion of patients with normal cognitive function had received influenza vaccinations. Furthermore, GDF-15 levels inversely correlated with MMSE score. Right ventricular diameter was negatively correlated, while hemoglobin levels were positively correlated with both MoCA and MMSE scores. Logistic regression analysis identified increased GDF-15 levels, older age, and advanced New York Heart Association (NYHA) classes as predictors of higher cognitive dysfunction risk, whereas influenza vaccination was linked to a reduced risk of cognitive dysfunction. CONCLUSION: Cognitive dysfunction in elderly patients with heart failure may be influenced by factors such as age, right ventricular enlargement, anemia, NYHA functional class, and levels of GDF-15 and NT-proBNP.

Serum Markers of Neurodegeneration Are Strongly Linked to Heart Failure Severity and Outcome.

BACKGROUND: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. OBJECTIVES: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aß40), and amyloid beta 42 (Aß42) in a large, well-characterized cohort. METHODS: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters. RESULTS: All markers, but not the Aß42:Aß40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aß40: 3.90 [95% CI: 2.27-6.72], and Aß42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aß40: 3.13 [95% CI: 1.84-5.34], and Aß42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aß40, Aß42, and the Aß42:Aß40 ratio were significantly lower (P < 0.05 for all). CONCLUSIONS: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function.

Cognitive profile, neuroimaging and fluid biomarkers in post-acute COVID-19 syndrome.

We aimed to characterize the cognitive profile of post-acute COVID-19 syndrome (PACS) patients with cognitive complaints, exploring the influence of biological and psychological factors. Participants with confirmed SARS-CoV-2 infection and cognitive complaints ≥ 8 weeks post-acute phase were included. A comprehensive neuropsychological battery (NPS) and health questionnaires were administered at inclusion and at 1, 3 and 6 months. Blood samples were collected at each visit, MRI scan at baseline and at 6 months, and, optionally, cerebrospinal fluid. Cognitive features were analyzed in relation to clinical, neuroimaging, and biochemical markers at inclusion and follow-up. Forty-nine participants, with a mean time from symptom onset of 10.4 months, showed attention-executive function (69%) and verbal memory (39%) impairment. Apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%) were prevalent. Visual memory (8%) correlated with total gray matter (GM) and subcortical GM volume. Neuronal damage and inflammation markers were within normal limits. Over time, cognitive test scores, depression, apathy, anxiety scores, MRI indexes, and fluid biomarkers remained stable, although fewer participants (50% vs. 75.5%; p = 0.012) exhibited abnormal cognitive evaluations at follow-up. Altered attention/executive and verbal memory, common in PACS, persisted in most subjects without association with structural abnormalities, elevated cytokines, or neuronal damage markers.

Inflammation at diagnosis and cognitive impairment two years later in breast cancer patients from the Canto-Cog study.

BACKGROUND: Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. METHODS: Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. RESULTS: Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06-7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05-5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43-36.6, p = 0.010). CONCLUSIONS: In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.

U-shaped relationship between non-high-density lipoprotein cholesterol and cognitive impairment in Chinese middle-aged and elderly: a cross-sectional study.

BACKGROUND: The relationship between blood lipids and cognitive function has long been a subject of interest, and the association between serum non-high-density lipoprotein cholesterol (non-HDL-C) levels and cognitive impairment remains contentious. METHODS: We utilized data from the 2011 CHARLS national baseline survey, which after screening, included a final sample of 10,982 participants. Cognitive function was assessed using tests of episodic memory and cognitive intactness. We used multiple logistic regression models to estimate the relationship between non-HDL-C and cognitive impairment. Subsequently, utilizing regression analysis results from fully adjusted models, we explored the nonlinear relationship between non-HDL-C as well as cognitive impairment using smooth curve fitting and sought potential inflection points through saturation threshold effect analysis. RESULTS: The results showed that each unit increase in non-HDL-C levels was associated with a 5.5% reduction in the odds of cognitive impairment (OR = 0.945, 95% CI: 0.897-0.996; p < 0.05). When non-HDL-C was used as a categorical variable, the results showed that or each unit increase in non-HDL-C levels, the odds of cognitive impairment were reduced by 14.2%, 20.9%, and 24% in the Q2, Q3, and Q4 groups, respectively, compared with Q1. In addition, in the fully adjusted model, analysis of the potential nonlinear relationship by smoothed curve fitting and saturation threshold effects revealed a U-shaped relationship between non-HDL-C and the risk of cognitive impairment, with an inflection point of 4.83. Before the inflection point, each unit increase in non-HDL-C levels was associated with a 12.3% decrease in the odds of cognitive impairment. After the tipping point, each unit increase in non-HDL-C levels was associated with an 18.8% increase in the odds of cognitive impairment (All p < 0.05). CONCLUSION: There exists a U-shaped relationship between non-HDL-C and the risk of cognitive impairment in Chinese middle-aged and elderly individuals, with statistical significance on both sides of the turning points. This suggests that both lower and higher levels of serum non-high-density lipoprotein cholesterol increase the risk of cognitive impairment in middle-aged and elderly individuals.

The Role of the Lipid Profile and Oxidative Stress in Fatigue, Sleep Disorders and Cognitive Impairment in Patients with Multiple Sclerosis.

The aim of this study is to investigate the relationship of the lipid profile, dysfunctional high-density lipoprotein, ischaemia-modified albumin and thiol-disulfide homeostasis with cognitive impairment, fatigue and sleep disorders in patients with multiple sclerosis. The cognitive functions of patients were evaluated with the Brief International Cognitive Assessment for Multiple Sclerosis battery. Fatigue was evaluated with the Fatigue Severity Scale and the Fatigue Impact Scale. The Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale were used to assess patients' sleep disturbance. Peripheral blood samples were collected, and lipid levels and myeloperoxidase and paraoxonase activity were measured. The myeloperoxidase/paraoxonase ratio, which indicates dysfunctional high-density lipoprotein, was calculated. Thiol-disulfide homeostasis and ischaemia-modified albumin were measured.
We did not identify any relationship between dysfunctional high-density lipoprotein and the physical disability, cognitive decline, fatigue and sleep problems of multiple sclerosis. Thiol-disulfide homeostasis was associated with cognitive scores. The shift of the balance towards disulfide was accompanied by a decrease in cognitive scores. On the other hand, we did not detect any relationship between fatigue and sleep disorders and thiol-disulfide homeostasis. Our findings revealed a possible correlation between cognitive dysfunction and thiol-disulfide homeostasis in multiple sclerosis patients.

Low testosterone levels relate to poorer cognitive function in women in an APOE-ε4-dependant manner.

BACKGROUND: Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer's disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone's effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype. METHODS: Five hundred and sixty one participants aged 55-90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language. RESULTS: We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males. CONCLUSIONS: Findings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone's role in cognitive health.

Sex differences often suggest a role of sex hormones, and in Alzheimer's Disease (AD) research, women show higher disease prevalence, accelerated cognitive decline, and an enhanced effect of the strongest genetic risk factor for AD, the apolipoprotein E ε4 allele (APOE-ε4). Testosterone, largely regarded as a "male" sex hormone, has demonstrated protective effects against AD in rodent studies including both sexes. However, human research often only includes males, limiting our understanding of testosterone's effect on AD risk and cognitive function. In this study, we investigated whether testosterone levels in the blood relate to cognitive performance measuring overall (global) cognition, verbal memory (remembering word lists or stories), executive function (complex thinking/multitasking), processing speed (how quickly one completes thinking tasks), and language (naming objects) in both sexes. We also tested whether this relationship is influenced by the APOE-ε4 genetic risk factor. We found that in females carrying APOE-ε4, lower testosterone levels related to worse performance on global cognition, processing speed, and verbal memory tests; however, testosterone levels did not relate to cognitive performance on any test in males nor in females without the APOE-ε4 genetic risk factor. Our findings suggest that the lower testosterone levels may be a contributing factor to worse AD outcomes in women, particularly for those at higher genetic risk for AD. Our results also demonstrate the importance of including female participants and considering the APOE-ε4 genetic risk factor when studying testosterone and brain health.

Serum albumin and white matter hyperintensities.

People living with HIV and those diagnosed with alcohol use disorders (AUD) relative to healthy individuals commonly have low levels of serum albumin, substantiated as an independent predictor of cardiovascular events. White matter hyperintensities (WMH)-a neuroimaging feature of cerebral small vessel disease-are also related to cardiovascular disease. Despite consensus regarding associations between high levels of urine albumin and WMH prevalence, and low serum albumin levels and impaired cognitive functioning, relations between serum albumin and WMH burdens have rarely been evaluated. Here, a sample including 160 individuals with AUD, 142 living with HIV, and 102 healthy controls was used to test the hypothesis that serum albumin would be inversely related to WMH volumes and directly related to cognitive performance in the two diagnostic groups. Although serum albumin and periventricular WMH volumes showed an inverse relationship in both AUD and HIV groups, this relationship persisted only in the HIV group after consideration of traditional cardiovascular (i.e., age, sex, body mass index (BMI), nicotine use, hypertension, diabetes), study-relevant (i.e., race, socioeconomic status, hepatitis C virus status), and disease-specific (i.e., CD4 nadir, HIV viral load, HIV duration) factors. Further, serum albumin contributed more significantly than periventricular WMH volume to variance in performance on a verbal learning and memory composite score in the HIV group only. Relations in both HIV and AUD groups between albumin and hematological red blood cell markers (e.g., hemoglobin, hematocrit) suggest that in this sample, serum albumin reflects hematological abnormalities. Albumin, a simple serum biomarker available in most clinical settings, may therefore help identify periventricular WMH burden and performance levels in specific cognitive domains in people living with HIV. Whether serum albumin contributes mechanistically to periventricular WMH in HIV will require additional investigation.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study.

BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

What Are the Reliable Plasma Biomarkers for Mild Cognitive Impairment? A Clinical 4D Proteomics Study and Validation.

Objective: At present, Alzheimer's disease (AD) lacks effective treatment means, and early diagnosis and intervention are the keys to treatment. Therefore, for mild cognitive impairment (MCI) and AD patients, blood sample analysis using the 4D nonstandard (label-free) proteomic in-depth quantitative analysis, looking for specific protein marker expression differences, is important. These marker levels change as AD progresses, and the analysis of these biomarkers changes with this method, which has the potential to show the degree of disease progression and can be used for the diagnosis and preventive treatment of MCI and AD. Materials and Methods: Patients were recruited according to the inclusion and exclusion criteria and divided into three groups according to scale scores. Elderly patients diagnosed with AD were selected as the AD group (n = 9). Patients diagnosed with MCI were classified into the MCI group (n = 10). Cognitively healthy elderly patients were included in the normal cognition control group (n = 10). Patients' blood samples were used for 4D label-free proteomic in-depth quantitative analysis to identify potential blood biomarkers. The sample size of each group was expanded (n = 30), and the selected biomarkers were verified by enzyme-linked immunosorbent assay (ELISA) to verify the accuracy of the proteomic prediction. Results: Six specific blood markers, namely, APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8, were detected by 4D label-free proteomic quantitative analysis. These markers showed a statistically significant upregulation trend in the MCI and AD groups compared with the normal cognition control group (P < 0.05). ELISA results showed that the levels of these six proteins in the MCI group were significantly higher than those in the normal cognition control group, and the levels of these six proteins in the AD group were significantly higher than those in the MCI group (P < 0.05). Conclusion: The plasma levels of APOE, MMP9, UBR5, PLA2G7, STAT5B, and S100A8 in cognitively healthy elderly patients and patients with MCI and AD were significantly different and, more importantly, showed a trend of increasing expression. These results indicate that these six human plasma markers have important diagnostic and therapeutic potential in the identification of cognitive impairment and have value for in-depth research and clinical application.

Serum proteomics study on cognitive impairment after cardiac valve replacement surgery: a prospective observational study.

Objective: The incidence of perioperative neurocognitive disorders (PND) is high, especially after cardiac surgeries, and the underlying mechanisms remain elusive. Here, we conducted a prospective observational study to observe serum proteomics differences in PND patients after cardiac valve replacement surgery. Methods: Two hundred and twenty-six patients who underwent cardiac valve surgery were included. They were categorized based on scoring into non-PND group (group non-P) and PND group (group P'). The risk factors associated with PND were analyzed. These patients were further divided into group C and group P by propensity score matching (PSM) to investigate the serum proteome related to the PND by serum proteomics. Results: The postoperative 6-week incidence of PND was 16.8%. Risk factors for PND include age, chronic illness, sufentanil dosage, and time of cardiopulmonary bypass (CPB). Proteomics identified 31 down-regulated proteins and six up-regulated proteins. Finally, GSTO1, IDH1, CAT, and PFN1 were found to be associated with PND. Conclusion: The occurrence of PND can impact some oxidative stress proteins. This study provided data for future studies about PND to general anaesthesia and surgeries.

Association between depressive symptoms and cognitive function in the older population, and the mediating role of neurofilament light chain: Evidence from NHANES 2013-2014.

OBJECTIVE: This study aimed to investigate the potential mediating role of the neurofilament light chain (NfL) level between depressive symptoms and cognitive function in older population. METHODS: A total of 495 adults (age ≥60 years) from the National Health and Nutrition Examination Survey (NHANES) participated in this study. Cognitive function was assessed using a combination of the Animal Fluency Test (AFT), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and the Digit Symbol Substitution Test (DSST). Word List Learning Test. Patient Health Questionnaire-9 (PHQ-9) was used to assess depressive symptoms. Data on serum NfL(sNfL) were collected. Multiple linear regressions and mediation analysis were utilized to examine the associations. RESULTS: After adjusting for potential confounding factors, the proportions mediated by the sNfL level between depressive symptoms and cognitive function was 19.65 %. The indirect effect mediated by the sNfL level between depressive symptoms and cognitive function was significant (ß[95 % CI]:-0.0089 [-0.0191, -0.0017],p = 0.040), while the direct effect in the absence of sNfL was non-significant (ß[95 % CI]: -0.0365 [-0.0739 0.0008],p = 0.055). LIMITATIONS: This is an explorative cross-sectional study with its limits in generalizability and ability to establish definitive causal associations. The results should be interpreted with caution due to the constraints imposed by the characteristics of the population with a relatively low overall level of depressive symptoms. CONCLUSION: The sNfL level, depressive symptoms, and cognitive decline are interconnected, and the sNfL level could mediate the relationship between depressive symptoms and cognitive decline among older adults.

[A cohort study of association between triglyceride glucose index-waist to height ratio and cognitive impairment in middle-aged and elderly population in China].

Objective: To explore the association between triglyceride glucose index (TyG)- waist to height ratio (WHtR)(TyG-WHtR) and cognitive impairment in middle-aged and elderly population. Methods: A cohort database was constructed using the data from the China Health and Retirement Longitudinal Study, with 8 946 participants in 2011 and 2015 as the baseline population. Cox proportional hazards regression models were used to estimate the association between TyG-WHtR levels at baseline and the risk of cognitive impairment in middle-aged and elderly population. The analysis was stratified by age and gender, respectively. Results: A total of 8 946 participants were included, with an average follow-up of 7.08 person-years and incidence density of cognitive impairment for 21.15 per 1 000 person-years. Compared with the Q1 level of TyG-WHtR, its Q3 and Q4 level increased the risk of cognitive impairment by 32% (HR=1.32, 95%CI: 1.09-1.60) and 47% (HR=1.47, 95%CI: 1.14-1.91), respectively. Trend test showed that the risk of cognitive impairment increased with the increase of TyG-WHtR level, and there was a dose-response relationship (P=0.001). Stratified analysis showed that in the population aged 45-59 years, compared with the Q1 level of TyG-WHtR, its Q3 level increased the risk of cognitive impairment by 34% (HR=1.34, 95%CI: 1.02-1.78). In the population aged 60 years and above, compared with the Q1 level, its Q3 and Q4 level increased the risk of cognitive impairment by 31% (HR=1.31, 95%CI: 1.01-1.72) and 63% (HR=1.63, 95%CI: 1.15-2.31), respectively. In the male group, there was no significant association between TyG-WHtR level and the risk of cognitive impairment (P>0.05). In the female group, compared with the Q1 level of TyG-WHtR, its Q4 level increased the risk of cognitive impairment by 76% (HR=1.76, 95%CI: 1.26-2.46). Conclusions: Middle-aged and elderly population with a higher TyG-WHtR level may increase the risk of cognitive impairment, and there were age and sex differences. Early cardiovascular health management and scientific and reasonable weight management are of great significance to preventing cognitive impairment.

Plasma BDNF/Irisin Ratio Associates with Cognitive Function in Older People.

Background: Reliable blood biomarkers are crucial for early detection and treatment evaluation of cognitive impairment, including Alzheimer's disease and other dementias. Objective: To examine whether plasma biomarkers and their combination are different between older people with mild cognitive impairment (MCI) and cognitively normal individuals, and to explore their relations with cognitive performance. Methods: This cross-sectional study included 250 older adults, including 124 participants with MCI, and 126 cognitively normal participants. Plasma brain-derived neurotrophic factor (BDNF), irisin and clusterin were measured, and BDNF/irisin ratio was calculated. Global cognition was evaluated by the Montreal Cognitive Assessment. Results: Plasma irisin levels, but not BDNF, were significantly different between MCI group and cognitively normal group. Higher irisin concentration was associated with an increased probability for MCI both before and after controlling covariates. By contrast, plasma BDNF concentration, but not irisin, was linearly correlated with cognitive performance after adjusting for covariates. Higher BDNF/irisin ratios were not only correlated with better cognitive performance, but also associated with lower risks of MCI, no matter whether we adjusted for covariates. Plasma BDNF and irisin concentrations increased with aging, whereas BDNF/irisin ratios remained stable. No significant results of clusterin were observed. Conclusions: Plasma BDNF/irisin ratio may be a reliable indicator which not only reflects the odds of the presence of MCI but also directly associates with cognitive performance.

Non-linear relationship of serum albumin-to-globulin ratio and cognitive function in American older people: a cross-sectional national health and nutrition examination survey 2011-2014 (NHANES) study.

Background: Inflammation and liver function are associated with cognitive decline and dementia. Little is known about the serum albumin-to-globulin ratio on cognitive function. Objective: The objective of this study was to investigate the association between albumin-to-globulin ratio and cognitive function among the American older people. Methods: The public data available on the US National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014 was used for this cross-sectional study. Participants aged ≥60 years completed the cognitive function assessments, including word learning and recall modules from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the animal fluency (AF) test, and the digit symbol substitution test (DSST). A composite cognition score was calculated to evaluate global cognition. The univariate and multivariate linear regression analysis, curve fitting, a threshold effect, along with a subgroup analysis and interaction tests were conducted. Results: Serum albumin-to-globulin ratio (per 0.1 unit) was positively associated DSST score (ß = 0.36, 95% CI: 0.21, 0.51), AF score (ß = 0.1, 95% CI: 0.04, 0.16) and global cognition score (ß = 0.05, 95% CI: 0.02, 0.07), after being fully adjusted, while albumin-to-globulin ratio was not related to CERAD score (ß = 0.05, 95% CI: -0.02, 0.12). A non-linear was observed in the dose-response relationship between albumin-to-globulin ratio and global cognition (P for non-linearity < 0.001). The subgroup analysis was overall stable, yet the interaction test was significant for age on global cognition (P for interaction = 0.036). Conclusion: The findings of this cross-sectional study suggested a positive and non-linear association between albumin-to-globulin ratio and cognitive function in the American older people. Maintaining albumin-to-globulin ratio with an appropriate range may be one of the therapeutic strategies to limit the progression of cognitive decline for the older people.